Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13: 423-430

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2010; 13(4):423-30. DOI: 10.1038/nn.2514
Source: PubMed


Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.

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Available from: Yu Zhou, Sep 19, 2014
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    • "Changes in DNA methylation and expression of hippocampal Bdnf are also associated with object recognition memory (Munoz et al., 2010) and the memory of traumatic experiences (Roth et al., 2011). As further evidence for the role of DNA methylation in memory processes, mice with disruptions in proteins associated with DNA methylation (including MeCP2 and DNMT1) show impairments in long-term potentiation and fear memory formation (Feng et al., 2010; Moretti et al., 2006; Nelson and Monteggia, 2011). Memory dysfunction in aged rats has also been linked to aberrant changes in hippocampal DNA methylation (Penner et al., 2011). "
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    ABSTRACT: Epigenetic mechanisms including altered DNA methylation are critical for altered gene transcription subserving synaptic plasticity and the retention of learned behavior. Here we tested the idea that one role for activity-dependent altered DNA methylation is stabilization of cognition-associated hippocampal place cell firing in response to novel place learning. We observed that a behavioral protocol (spatial exploration of a novel environment) known to induce hippocampal place cell remapping resulted in alterations of hippocampal Bdnf DNA methylation. Further studies using neurophysiological in vivo single unit recordings revealed that pharmacological manipulations of DNA methylation decreased long-term but not short-term place field stability. Together our data highlight a role for DNA methylation in regulating neurophysiological spatial representation and memory formation.
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    • "Developmental changes of DNMT1 and DNMT3A proteins in mouse hippocampus and neocortex regions We measured the levels of DNMT1 and DNMT3A, enzymes involved in DNA methylation (Biniszkiewicz et al. 2002; Feng et al. 2010), during various stages of brain development . DNMT1 antibody recognized a major band running at 200 kDa (predicted to run at ~183 kDa) as observed in several previous studies (Robertson et al. 2000; Liu et al. 2003). "
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    • "It has been demonstrated that the DNMTs play an important role in synaptic function (Feng et al., 2010). Moreover, we observed that perinatal HFD continued into adulthood decreased the expression of synaptotagmin 4 and synaptophysin , two major molecules involved in vesicle exocytosis. "
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